A Scalable Membrane Pervaporation Approach for Continuous Flow Olefin Metathesis

Article abstract of DOI:10.1021/acs.oprd.0c00061

The translation of olefin metathesis reactions from the laboratory to process scale has been challenging with traditional batch techniques. In this contribution, we describe a continuous membrane reactor design that selectively permeates the ethylene byproduct from metathetical processes, thereby overcoming the mass-transport limitations that have negatively influenced the efficiency of this transformation in batch vessels. The membrane sheet-in-frame pervaporation module yielded turnover numbers of >7500 in the case of diethyl diallylmalonate ring-closing metathesis. The preparation of more challenging, low-effective-molarity substrates, a cyclooctene and a 14-membered macrocyclic lactone, was also effective. A comparison of optimal membrane reactor conditions to a sealed tubular reactor revealed that the benefits of ethylene removal are most apparent at low reaction concentrations.

Full text of DOI:10.1021/acs.oprd.0c00061

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Communication
A Scalable Membrane Pervaporation Approach for Continuous Flow
Olefin Metathesis
Christopher P. Breen, Christine Parrish, Ning Shangguan, Sudip Majumdar, Hannah Murnen,
Timothy F. Jamison,* and Matthew M. Bio*
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ABSTRACT: The translation of olefin metathesis reactions from the laboratory to process scale has been challenging with
traditional batch techniques. In this contribution, we describe a continuous membrane reactor design that selectively permeates the
ethylene byproduct from metathetical processes, thereby overcoming the mass-transport limitations that have negatively influenced
the efficiency of this transformation in batch vessels. The membrane sheet-in-frame pervaporation module yielded turnover numbers
of >7500 in the case of diethyl diallylmalonate ring-closing metathesis. The preparation of more challenging, low-effective-molarity
substrates, a cyclooctene and a 14-membered macrocyclic lactone, was also effective. A comparison of optimal membrane reactor
conditions to a sealed tubular reactor revealed that the benefits of ethylene removal are most apparent at low reaction
concentrations.
KEYWORDS: olefin metathesis, continuous flow, membrane separation, macrocyclization
INTRODUCTION
■
Catalytic olefin metathesis is a well-established synthetic
strategy to access valuable molecular targets.1 Ring-closing
metathesis (RCM) is perhaps the most utilized transformation
for the preparation of small molecules from discovery to
process and is of great interest to the fragrance industry.2
Despite the efficiency of olefin metathesis processes on the
laboratory scale, successful implementation on the industrial
scale has been challenging.2,3
In 2005, a Boehringer Ingelheim team identified a set of
barriers to scaling the macrocyclic RCM (mRCM) to yield the
hepatits C virus protease inhibitor BILN 2061 ZW in batch.4
Laboratory-scale efforts proceeded smoothly, but the reaction
performance suffered upon batch scaling to meet production
needs. Extended reaction times and a higher catalyst loading
were required to achieve the target reaction performance. The
poor scaling behavior was partly attributed to inefficient mass
transfer of ethylene from the reaction medium in 3000 L
process vessels, where it promotes catalyst decomposition and
may facilitate undesirable alkene isomerization.5−7 The well-
documented negative effects of persistent ethylene in
metathetical processes as well as our interest in expanding
Figure 1. (A) Ru catalysts for homogeneous olefin metathesis. (B)
Different reactor designs to achieve continuous ring-closing meta-
thesis.
the scope of continuous processing techniques prompted us to
contemplate a reactor platform to address this mass-transport
problem.8−10
Prior work in the area of continuous olefin metathesis shows
a clear dependence of the reaction outcome on the reactor
Special Issue: Flow Chemistry Enabling Efficient
Synthesis
design (Figure 1). Heterogeneous Grubbs−Hoveyda-type
catalysts used in recirculating packed-bed reactor configu-
rations were among the first examples.11−15 While effective, the
Received: February 19, 2020
preferred catalysts were not commercially available and had
limited stability. Reports from Lamaty16 and Collins17 showed
that flow reactions in sealed tubular reactors provide good
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A

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throughput in RCM and mRCM reactions with homogeneous
catalysts with heating and a relatively high catalyst loading. In
2010, the Fogg group leveraged flow technology in a
continuously stirred tank reactor with Grubbs catalyst 4 to
significantly improve the unbiased mRCM reaction of 7
compared with the batch protocol (Figure 1B).18 Notably, a
large reactor headspace (∼50% v/v) constantly swept with
argon was required to purge ethylene. However, unfavorable
surface-area-to-volume ratios in larger process vessels may
challenge the scalability of this approach. In 2014, Skowerski
reported that a Teflon AF-2400 tube-in-tube reactor capable of
ethylene removal can be used to perform RCM, mRCM, and
cross-metathesis reactions.19 However, scaling of this technol-
ogy is impractical because of tubing fragility, high costs, and
limited availability.
We set out to design a practical and scalable flow technology
approach for RCM wherein good catalytic performance would
be enabled by continuous ethylene removal in a manner that
would be sufficiently robust for process intensification. To this
end, we established a collaboration with Compact Membrane
Systems (CMS), a team with experience in developing
functional polymer membranes for selective permeation
processes on process scale.20 These commercially available
materials are scalable by design, tolerate high pressure and
temperatures, have reactor design flexibility through custom
engineering solutions, and display excellent chemical compat-
ibility. Specifically, we sought to apply this technology in
creating a unique process window wherein the semipermeable
membrane would facilitate continuous ethylene removal from
the reaction medium, thereby driving metathesis reactions to
high conversion and attenuating ethylene-mediated catalyst
decomposition pathways. Herein we describe the successful
development of a continuous RCM platform utilizing this
membrane pervaporation technology.
Figure 2. RCM reaction conversion profiles with different modes of
ethylene removal or addition. Conversion = 100%·(area for 12)/(area
1
for 11 + 12) by H NMR analysis.
disk (Ø = 47 mm) served as a test platform. The membrane is
a composite material composed of a perfluorinated polymer
coated on a chemically resistant microporous layer that
provides structural integrity. Ethylene permeation results
expressed in gas permeance units (GPU) as well as surface-
area-dependent mass flow are shown in Table 1. The ethylene
Table 1. Gas-Phase Ethylene Permeation Studies Using the
Membrane Sheet-in-Frame Module
RESULTS AND DISCUSSION
■
Before testing the continuous membrane reactor, we evaluated
the influence of ethylene on the RCM reaction of diethyl
diallylmalonate (11) to yield cyclopentene 12 catalyzed by the
Grubbs−Hoveyda II catalyst 1 (Figure 2). A room-temper-
ature batch reaction with 0.1 mol % 1 and a gentle sparge of N2
resulted in rapid and complete (>99.8%) conversion of 11 to
12 within 30 min of reaction time. As expected, sealing the
reaction vessel negatively impacted the conversion. Saturating
the reaction medium with ethylene at ambient pressure
impeded the reaction and limited the conversion to ∼85%.
Applying ethylene to the headspace at a pressure of 20 psi
further impeded the reaction such that <50% conversion was
reached. Venting and sparging after 40 min under otherwise
identical conditions led to partially restored catalytic activity
once ethylene was removed. Finally, a flow reaction was
performed in a stainless steel tubular reactor, confirming the
deleterious effect of ethylene in a continuous reactor design.
These observations are consistent with Tulchinsky’s findings
that ethylene significantly contributes to Ru−methylidene-
mediated catalyst decay under continuous conditions,
ultimately limiting high catalyst turnover numbers (TONs).21
For our approach to mitigate the effects of trapped ethylene,
the rate of mass transport provided by the membrane would
have to approach or exceed the production rate. Thus, we first
sought to understand the ethylene permeation kinetics under
conditions relevant to olefin metathesis. A laboratory-scale
stainless steel sheet-in-frame module fitted with a membrane
a
b
entry
temp. (°C)
permeance (GPU)
ethylene flux (g·h−1·m−2
)
1
2
3
4
5
25
40
55
65
80
49.6
50.6
63.5
93.2
118
253
270
354
537
710
a
Temperatures were equilibrated for 30 min, after which the ethylene
flow was started and the permeation was equilibrated for 60 min
before flux measurements. Averages of two trials with different
membrane samples.
b
flux across the membrane above 65 °C suggests that useful
throughputs can be achieved. For example, the 47 mm
diameter membrane disk is capable of an ethylene flux of >43
mmol·h−1 at 80 °C under a back pressure of 20 psi.
The same membrane sheet-in-frame module was then fitted
for use as a continuous reactor. The RCM substrate and Ru
catalyst are pumped through a helical-type static mixer before
entering the membrane reactor. The reaction mixture then
passes over the membrane, where the generated ethylene
passes to the permeate chamber, which is constantly swept
with N2 metered by a mass flow controller (MFC) and flowing
countercurrent to the liquid retentate stream. Constantly
purging the permeate chamber provides a driving force for
B
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Table 2. Continuous RCM of Diethyl Diallylmalonate (11) Using the Membrane Sheet-in-Frame Reactor
a
b
b
c
entry
catalyst cat. loading (mol %) temp. (°C) back pressure (psi) N2 flow rate (mL/min) tR (min) yield of 12 (%)
yield of 11 (%)
TON
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
2
2
0.100
0.100
0.100
0.100
0.050
0.050
0.025
0.010
0.050
40
40
60
60
80
120
120
120
120
20
40
20
20
20
30
30
30
30
50
50
50
200
50
50
50
50
50
19.1
19.1
19.1
19.1
20.0
5.0
5.1
5.2
1.3
74.4
72.8
95.8
95.4
95.0
99.8
96.1
75.8
98.1
24.8
25.9
4.0
4.2
4.2
0.0
3.2
23.9
1.8
744
728
958
954
1900
1996
3844
7580
1962
a
b
1
All trials were equilibrated for 3tR before sampling for yield. Determined by quantitative H NMR analysis versus external benzyl benzoate.
c
Versus yield of 12.
diffusion by ensuring that the partial pressure of ethylene
across the membrane is maximized. The retentate stream is
kept under pressure through the use of an adjustable back-
pressure regulator (BPR). A diagram of this reactor design is
shown in Table 2.
bearing different ring sizes, alkene substitution, and heter-
oatom functionality (Table 3). The diene precursor of Boc-
Table 3. Substrate Scope of Continuous RCM Using the
Membrane Sheet-in-Frame Reactor
We first tested the influence of the nitrogen sweep rate and
applied back pressure (Table 2). It was initially suspected that
these parameters would affect the rate of ethylene flux, thus
controlling the reaction performance. A baseline experiment
performed with 0.1 mol % 1, RCM substrate 11 at 0.2 M in
toluene, and the membrane reactor at 40 °C resulted in a
74.4% yield of 12 in 19.1 min with unreacted 11 constituting
the mass balance (entry 1). The applied back pressure was
then increased from 20 to 40 psi with all of the other variables
unchanged (entry 2). A similar yield of 72.8% was observed for
12, indicating that varying the transmembrane pressure does
not change the reaction outcome.
Increasing the reactor temperature to 60 °C provided a
98.5% yield of 12, corresponding to a TON of 958 (entry 3).
In a subsequent experiment, the permeate chamber nitrogen
sweep rate was increased to 200 mL/min, which resulted in a
nearly identical yield of 12 (entry 4).
Ultimately, increased temperature provided a favorable
balance of short processing times and low catalyst loadings.
Lowering the loading of 1 to 0.05 mol % provided a 95.0%
yield of 12 after a residence time of 20 min at 80 °C (entry 5).
When the reaction temperature was increased to 120 °C, a
residence time of only 5.0 min was required to achieve 99.8%
yield at the same catalyst loading (entry 6). Further reducing
the loading of 1 to 0.025 mol % resulted in a slightly lower
yield in a similar residence time, with a TON of 3844 (entry
7).
[Ru-2] loading
(mol %)
tR
temp.
[final]
a
b
entry product
(min) (°C)
(mM)
yield (%)
1
2
3
4
13
14
15
16
0.10
0.10
0.25
1.0
7.0
5.3
5.3
90
100
110
110
200
50
50
5
90.3 [87]
98.0 [92]
92.4 [90]
89.1 [81]
10.5
a
All trials were equilibrated for 3tR before collection of analytical or
b
1
bulk samples. Determined by quantitative H NMR analysis versus
benzyl benzoate as an external standard. Isolated yields are given in
brackets.
protected dihydropyrrole 13 and other RCM substrates
bearing sterically accessible coordinating functional groups
often require higher catalyst loadings and longer processing
times compared with substrates such as 11. Nonetheless, 13
was obtained in >90% yield with 0.10 mol % 2. Dihydropyran
14 was produced in 98.0% yield at the same catalyst loading,
whereas 2.0 mol % Ru catalyst was used in previously reported
batch protocols.24 Dihydrobenzoxepine 15 was formed in good
yield with a notably shorter processing time and lower catalyst
loading compared with previous batch reports, which typically
employed ≥0.5 mol % catalyst and a reaction time of at least 8
h.25,26
Catalyst 2 gave improved kinetics compared with 1 via
electronic activation of the chelating benzylidene.22,23
A
loading of only 0.01 mol % provided modest yield of 12 but
displayed high catalytic efficiency with a TON of 7580 at
elevated temperature (entry 8). In an effort to balance the
catalyst efficiency with short processing times, we found that
0.05 mol % 2 provided a high yield of 12 in a residence time of
just 1.3 min (entry 9).
Lastly, we addressed the preparation of cyclooctene 16, a
substrate with an effective molarity (EM) of ≤23 mM.27
A
Having established suitable conditions for the facile RCM of
11, we next applied the system to more challenging substrates
significantly lower substrate concentration and elevated
catalyst loading were expected to promote the desired ring
C
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closing over the formation of acyclic diene metathesis
(ADMET) oligomers. Indeed, substrate concentrations above
10 mM provided good conversion but low yields of 16,
indicating that oligomerization was a significant competing
pathway. Lowering the substrate concentration to 5 mM with 1
mol % 2 provided the desired product in good yield.
Comparing the results obtained using a sealed stainless steel
tubular reactor against those obtained with the membrane
reactor emphasizes the performance gains provided by
ethylene removal (Figure 3). In all cases, the RCM product
catalyst 4 at 1 mol % loading provided an acceptable yield
with a residence time of 21 min at 100 °C (entry 1). The
selectivity for the desired cyclization over the formation of
ADMET oligomers was also good, in agreement with results
from the Fogg group.27 Both higher yield and better selectivity
at milder temperatures were obtained when indenylidene
catalyst 5 was employed at the same loading (entry 2).
We then evaluated contemporary cyclic alkyl amino carbene
(CAAC) catalyst28 6 and diiodo catalyst29 3 at the high
temperature of 120 °C and an unfavorable substrate
concentration of 10 mM (entries 3 and 4). Nearly 80% yield
of 18 was obtained when 6 was employed at 1 mol % loading.
Catalyst 3 similarly provided good selectivity and similar yield
but required only 0.5 mol % loading. Increasing the catalyst 3
loading and operating at a lower concentration of 17 allowed
for a shorter residence time (10.5 min) along with a higher
yield and better selectivity (entry 5). Interestingly, even a high
loading of 2 was not able to surpass the results obtained with
catalyst 3 (entry 6), likely because of the added stability
provided by the iodides.
A single membrane coupon provided robust, reproducible
performance throughout this body of work. Visualization of the
used membrane surface showed minor wear compared with an
unused sample, but the membrane was unaffected by fouling
despite extended operation under intensive conditions. The
selectivity for permeation of ethylene over other volatile
reaction components, such as toluene, was also unaffected over
time. Measurements of retained solvent mass after passage
through the membrane reactor at elevated temperature with a
nitrogen sweep of the permeate chamber showed a negligible
difference compared to the expected mass flow of the retentate
(see the Supporting Information). It follows that further
process controls that have been previously been required to
manage solvent volatilization in heated, sparged batches may
not be not be necessary with this reactor design. Toluene was
chosen as the exclusive solvent in this work because of its
general utility as a process solvent, but other industrially
preferred solvents that are compatible with metathetical
reactions, such as alkanes or esters, would also be suitable
for use in this system. While the reactor described herein was
fit for a proof-of-concept demonstration, a purpose-built
reactor featuring the same functional membrane technology
in a high-surface-area hollow fiber reactor design would likely
afford performance gains. Intensive effort to redesign and
fabricate new reactor designs to eliminate the disadvantages of
the current module is beyond the scope of this demonstration.
Figure 3. Comparison of yields using the membrane reactor vs the
stainless steel tubular reactor.
yield obtained using the membrane reactor was significantly
greater than that with the sealed tubular reactor. At low
substrate concentrations, the negative effects of ethylene are
expected to be more acute. As anticipated, the largest observed
yield difference occurred in the case of cyclooctene 16. Low-
EM substrates typically face the greatest reproducibility
challenges in batch reactors, so consistent performance of
our membrane reactor should provide a viable option for
reliable scaling.
We further explored challenging RCM substrates by
performing the macrocyclic RCM reaction to yield lactone
18, a substrate with a similarly low EM and relevance to the
fragrance industry (Table 4). Second-generation Grubbs
Table 4. Continuous mRCM of 17 Using the Membrane
Sheet-in-Frame Reactor
CONCLUSION
■
We have demonstrated RCM enabled by selective membrane
permeation of ethylene. Our reactor design takes advantage of
the commercially available and inherently scalable membranes
provided by Compact Membrane Systems. The stability and
excellent longevity of these membranes permits an expanded
thermal process window while also delivering selective and
high-flux ethylene permeation. The technology was success-
fully applied to the RCM of small, medium, and large rings
with good effect, achieving TONs of >7500 in the case of 12.
Notably, for this specific application we speculate that a small-
footprint hollow fiber reactor module could improve our
reactor design. Lastly, the generality of the membrane
technology discussed herein suggests opportunities in other
reaction types that would benefit from the selective removal of
cat.
tR
temp.
[final]
yield of 18 selectivity
b c
a
entry
(mol %) (min)
(°C)
(mM)
(%)
(%)
1
2
3
4
5
6
4 (1.0)
5 (1.0)
6 (1.0)
3 (0.5)
3 (1.5)
2 (2.0)
21.0
21.0
21.0
21.0
10.5
21.0
100
90
120
120
100
100
5
5
10
10
5
77.8
84.5
79.7
78.0
95.4
87.3
81.5
86.1
81.5
81.5
98.2
90.2
5
a
All experiments were equilibrated for 3tR before collection of
analytical samples. Determined by quantitative GC-FID analysis
versus external dodecane. Selectivity = 100%·(% yield/% con-
b
c
version).
D
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(5) Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.;
Grubbs, R. H. Decomposition of ruthenium olefin metathesis
catalysts. J. Am. Chem. Soc. 2007, 129, 7961−7968.
volatile reaction components while avoiding the penalties of
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general decomposition pathway for phosphine-stabilized metathesis
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Chem. Soc. 2016, 138, 14668−14677.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00061.
■
sı
(7) Hong, S. H.; Day, M. W.; Grubbs, R. H. Decomposition of a key
intermediate in ruthenium-catalyzed olefin metathesis reactions. J.
Am. Chem. Soc. 2004, 126, 7414−7415.
Characterization and images of the membrane pervapo-
ration reactor, synthetic procedures, characterization
data, and NMR spectra (PDF)
(8) Morse, P. D.; Beingessner, R. L.; Jamison, T. F. Enhanced
reaction efficiency in continuous flow. Isr. J. Chem. 2017, 57, 218−
227.
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technology as a tool for the safe manufacturing of active
pharmaceutical ingredients. Angew. Chem., Int. Ed. 2015, 54 (23),
6688−728.
AUTHOR INFORMATION
Corresponding Authors
■
Matthew M. Bio − Snapdragon Chemistry, Inc., Waltham,
Massachusetts 02451, United States; orcid.org/0000-0002-
6637-3489; Email: matt.bio@snapdragonchemistry.com
Timothy F. Jamison − Department of Chemistry, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02139,
United States; orcid.org/0000-0002-8601-7799;
Email: tfj@mit.edu
(10) Fitzpatrick, D. E.; Ley, S. V. Engineering chemistry for the
future of chemical synthesis. Tetrahedron 2018, 74 (25), 3087−3100.
(11) Michrowska, A.; Mennecke, K.; Kunz, U.; Kirschning, A.; Grela,
K. A new concept for the noncovalent binding of a ruthenium-based
olefin metathesis catalyst to polymeric phases: preparation of a
catalyst on raschig rings. J. Am. Chem. Soc. 2006, 128, 13261−13267.
(12) Schoeps, D.; Buhr, K.; Dijkstra, M.; Ebert, K.; Plenio, H.
Batchwise and continuous organophilic nanofiltration of grubbs-type
olefin metathesis catalysts. Chem. - Eur. J. 2009, 15, 2960−2965.
Authors
Christopher P. Breen − Snapdragon Chemistry, Inc., Waltham,
Massachusetts 02451, United States; Department of Chemistry,
Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States
Christine Parrish − Compact Membrane Systems, Newport,
Delaware 19804, United States
Ning Shangguan − Compact Membrane Systems, Newport,
Delaware 19804, United States
Sudip Majumdar − Compact Membrane Systems, Newport,
Delaware 19804, United States
̈
(13) Duque, R.; Ochsner, E.; Clavier, H.; Caijo, F.; Nolan, S. P.;
Mauduit, M.; Cole-Hamilton, D. J. Continuous flow homogeneous
alkene metathesis with built-in catalyst separation. Green Chem. 2011,
13, 1187−1195.
́
(14) Borre, E.; Rouen, M.; Laurent, I.; Magrez, M.; Caijo, F.;
́
Crevisy, C.; Solodenko, W.; Toupet, L.; Frankfurter, R.; Vogt, C.;
Kirschning, A.; Mauduit, M. A fast-initiating ionically tagged
ruthenium complex: a robust supported pre-catalyst for batch-process
and continuous-flow olefin metathesis. Chem. - Eur. J. 2012, 18,
16369−16382.
(15) Autenrieth, B.; Frey, W.; Buchmeiser, M. R. A dicationic
ruthenium alkylidene complex for continuous biphasic metathesis
using monolith-supported ionic liquids. Chem. - Eur. J. 2012, 18,
14069−14078.
Hannah Murnen − Compact Membrane Systems, Newport,
Delaware 19804, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00061
(16) Drop, M.; Bantreil, X.; Grychowska, K.; Mahoro, G. U.;
Colacino, E.; Pawłowski, M.; Martinez, J.; Subra, G.; Zajdel, P.;
Lamaty, F. Continuous flow ring-closing metathesis, an environ-
mentally-friendly route to 2,5-dihydro-1H-pyrrole-3-carboxylates.
Green Chem. 2017, 19, 1647−1652.
Notes
The authors declare no competing financial interest.
́
ACKNOWLEDGMENTS
(17) Morin, E.; Sosoe, J.; Raymond, M.; Amorelli, B.; Boden, R. M.;
■
Collins, S. K. Synthesis of a renewable macrocyclic musk: evaluation
of batch, microwave, and continuous flow strategies. Org. Process Res.
Dev. 2019, 23, 283−287.
(18) Monfette, S.; Eyholzer, M.; Roberge, D. M.; Fogg, D. E. Getting
ring-closing metathesis off the bench: reaction-reactor matching
transforms metathesis efficiency in the assembly of large rings. Chem. -
Eur. J. 2010, 16, 11720−11725.
C.P.B. is grateful for support from Snapdragon Chemistry, Inc.
during the summer of 2019 and the Moore Fellowship from
the MIT Department of Chemistry. We thank Yuan-Qing Fang
(Snapdragon Chemistry, Inc.), David Ford (Snapdragon
Chemistry, Inc.), and Rachel L. Beingessner (MIT) for helpful
discussions throughout this work.
(19) Skowerski, K.; Czarnocki, S. J.; Knapkiewicz, P. Tube-in-tube
reactor as a useful tool for homo- and heterogeneous olefin metathesis
under continuous flow mode. ChemSusChem 2014, 7, 536−542.
(20) Li, B.; Guinness, S. M.; Hoagland, S.; Fichtner, M.; Kim, H.; Li,
S.; Maguire, R. J.; McWilliams, J. C.; Mustakis, J.; Raggon, J.; Campos,
D.; Voss, C. R.; Sohodski, E.; Feyock, B.; Murnen, H.; Gonzalez, M.;
Johnson, M.; Lu, J.; Feng, X.; Sun, X.; Zheng, S.; Wu, B. Continuous
production of anhydrous tert-butyl hydroperoxide in nonane using
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